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Old 06-16-2015, 08:18 PM
gdpawel gdpawel is offline
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Default Top 10 Reasons Against Routine Genomic Profiling of Tumors in Patient Care

When they did comprehensive screening for gene mutations at MD Anderson, in a huge number of patients, they found an actionable target in 31%, but, of these 31%, only 10% responded to the targeted therapy. Overall, only 2.4% of all the patients receiving genomic profiling had a response. This is absolutely horrible. I think that genomic profiling is in general a scam, yet virtually everyone is doing it. I think that certain types of targeted genomic profiling is probably worthwhile -- e.g. EGFR mutations in lung cancer, but phenotype analysis can test for the same drugs using cell culture as a platform.

San Francisco, CA—Neal J. Meropol, MD, of the University Hospitals Seidman Cancer Center, and Case Western Reserve University, Cleveland, OH, has long advocated against unnecessary treatment and testing of patients with cancer. At the 2015 Gastrointestinal Cancers Symposium, Dr Meropol outlined his reasons why clinicians should not bend to pressure to routinely test all tumors. “Here are my top 10 reasons why I believe we are not ready for routine molecular profiling of tumors,” he told the audience, listing the following reasons.

1. Assay Platform Limitations

Variability in the sensitivity and specificity of the many platforms being promoted raises questions regarding analytic validation, said Dr Meropol, asking questions that raise concern. How are the genes selected for these panels? Does the platform look at the transcriptome or just the genome? Are we looking at epigenomic changes that may be relevant in selecting treatments? What is the turnaround time for the results? And what is the cost of these assays?

2. Tumors Are Heterogenous and Complex

Mutations in a tumor may be different between sites. “Although they may look the same under a microscope, colon cancers and gastric cancers are extremely complex, and extremely heterogenous in terms of their molecular profiles,” Dr Meropol said. Nor will finding a single driver mutation guarantee that a single drug intervention will be effective, because of “cross talk” between pathways occurring downstream of a key mutation. “If we’re going to use a tumor biopsy for selecting treatment for an individual patient,” he said. “This biopsy should be done proximate to the time that we’re going to intervene with a new therapy.”

3. We Don’t Know the Drivers

According to Dr Meropol, definitions used in the MATCH trial for identifying drivers to explore in a clinical trial are not yet good enough for routine care. “The reasons not to try it are that these are costly interventions, they may not work, they have side effects, and they provide false hope. This should not be our routine approach with patients,” he advised.

4. We Don’t Have the Evidence that Links Drugs to These Drivers

The best level evidence is an FDA-approved dyad, but Dr Meropol stressed that this level of evidence is missing in nearly all drug cases. “Even if an agent meets a clinical end point, and there’s evidence of target inhibition, and there’s plausible evidence of a predictive or selection assay or analyte,” he said, “until it’s been proved in a prospective clinical trial, the evidence may be viewed as weak in terms of routine clinical practice.” Preclinical evidence is an even poorer prognosticator for patient outcomes. Dr Meropol iterated the need for incentivizing the development of biomarkers worldwide.

5. Investigational Drugs Are Not Widely Available

There are limited clinical trial sites; patients have to seek studies and travel for them. “Not everybody lives in close proximity to a research center that has access to multiple clinical trials and new agents,” Dr Meropol said, “and getting compassionate access to a new drug in development is a logistically complicated process. It’s time-consuming and rather opaque.”

6. It Isn’t Practical to Screen Many to (Maybe) Help a Few

The evidence is simply not there at this time, he said, highlighting a phase 1 study conducted at M.D. Anderson Cancer Center that intended to show the benefit of identifying clinical trials that might be appropriate for patients’ tumors. Of the 1283 patients assessed, 31% had at least 1 mutation, and among those who could be matched for treatment, approximately 10% had an antitumor response. But the overall response rate based on matching was only 2.4%.

7. There Is No Mechanism to Pay for Drugs for Off-Label Use

Off-label use of expensive targeted agents is increasingly scrutinized by payers, and costs are falling on patients. “Recommending cancer drugs with high copays may not be ethical without strong evidence that it’s going to help that individual patient,” he said.

8. Drug Approval Based on Tumor Type, Not on Genotype

The current (and old) paradigm is histology-based and requires large prospective phase 3 trials to provide the level of evidence that leads to a FDA and worldwide drug approval. But an emerging paradigm for drug approval is genome-based, using small studies looking for big effect to make decisions, “but we’re simply not there yet,” he said.

9. No Statistical Approach to Interpreting a Series of Anecdotes

Dr Meropol asked: How much evidence is needed to conclude that a particular mutation should receive a particular therapy? How many patients are needed with outcome data across how many tissues of origin? And when looking at a major response, how can we distinguish between a fluke and an outcome that is real? The answers to these questions remain unknown.

10. Unintended Consequences for Patients

Given the potential for confusion over interpretation, it is important to know who is interpreting the data and making the recommendations. “We don’t want to give our patients false hope,” said Dr Meropol. “We don’t want to subject them to the risks of needless biopsies, and we don’t want to subject them to the financial burden of therapies and procedures that are not destined to help them.”

Source: Association for Value-Based Cancer Care (February 2015, Vol 6, No 1 - Personalized Medicine)
Gregory D. Pawelski

Last edited by gdpawel : 06-16-2015 at 08:27 PM. Reason: Post full article on forum board
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Old 06-22-2015, 11:11 PM
gdpawel gdpawel is offline
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The particular sequence of DNA that an organism possesses (genotype), or mutational assay, does not determine what bodily or behavioral form (phenotype), or cellular assay, the organism will finally display. Among other things, environmental influences can cause the suppression of some gene functions and the activation of others. The knowledge of genomic complexity tells us that genes and parts of genes interact with other genes, as do their protein products, and the whole system is constantly being affected by internal and external environmental factors. The gene may not be central to the phenotype at all, or at least it shares the spotlight with other influences. Environmental tissue and cytoplasmic factors clearly dominate the phenotypic expression processes, which may in turn, be affected by a variety of unpredictable protein-interaction events.

Until such time as cancer patients are selected for therapies predicted upon their own unique biology, we will confront one targeted drug after another. A better solution to this problem would be to investigate the targeting agents in each individual patient's tissue culture, alone and in combination with other drugs, to gauge the likelihood that the targeting will favorably influence each patient's outcome. Functionally (cellular assay) profiling these results in patients with a multitude type of cancers suggest this to be a highly productive direction.

There is a ray of hope with immunotherapy, after the elements of the cancer industry had put it under a breadbox for over twenty years. Immunotherapy actually does work. However, researchers have no idea why it benefits some people but not others, because releasing the brake facilitates an all-out attack by the immune system, it can cause serious side effects - colitis, skin rashes, impaired pituitary function - that must be managed. The key is identifying the individual patients who stand to benefit (not average populations). Certainly new approaches to immunotherapy are both needed and welcome. It's not the answer to all of cancer, certainly, but when it works, it's helpful.
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Old 07-20-2015, 01:42 PM
gdpawel gdpawel is offline
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Default SPARC Expression Analysis for Metastatic Pancreatic Cancer

A paper showing the worthlessness of gene mutation and/or expression markers for predicting response to the traditional cytotoxic anticancer drugs which constitute more than 90% of all drugs currently utilized in cancer chemotherapy:

SPARC Expression Did Not Predict Efficacy of nab-Paclitaxel Plus Gemcitabine or Gemcitabine Alone for Metastatic Pancreatic Cancer in an Exploratory Analysis of the Phase III MPACT Trial.


nab-Paclitaxel plus gemcitabine was superior to gemcitabine alone for patients with metastatic pancreatic cancer (MPC) in the phase III MPACT trial. This study evaluated the association of Secreted Protein Acidic and Rich in Cysteine (SPARC) levels with efficacy as an exploratory endpoint.

Patients with previously untreated MPC (N = 861) received nab-paclitaxel plus gemcitabine or gemcitabine alone. Baseline SPARC level was measured in the tumor stroma and epithelia (archival biopsies) and plasma. Experiments were performed in PC mouse models in which SPARC was intact or deleted.

SPARC was measured in the tumor stroma of 256 patients (30%), the tumor epithelia of 301 patients (35%), and plasma of 343 patients (40%). Stroma-evaluable samples were from metastases (71%), the pancreas (11%), or of unidentifiable origin (insufficient tissue to determine; 17%). For all patients, stromal SPARC level (high [n = 71] vs. low [n = 185]) was not associated with overall survival (OS; hazard ratio 1.019; P = 0.903); multivariate analysis confirmed this lack of association. There was no association between stromal SPARC level and OS in either treatment arm. Neither tumor epithelial SPARC nor plasma SPARC were associated with OS. Results from a SPARC knockout mouse model treated with nab-paclitaxel plus gemcitabine revealed no correlation between SPARC expression and tumor progression or treatment efficacy.

SPARC levels were not associated with efficacy in patients with MPC. This exploratory analysis does not support making treatment decisions regarding nab-paclitaxel plus gemcitabine or gemcitabine alone in MPC based on SPARC expression.

Source: American Association for Cancer Research.

Gregory D. Pawelski
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Old 07-20-2015, 01:57 PM
gdpawel gdpawel is offline
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Default The Frightening Truth About Genetic Testing

Genetic testing is now ordered in the treatment of numerous cancer types. Is it useful? Is it even reliable? Dr. John Marshall and world-class experts tackle key questions for practicing clinicians.

John L. Marshall, MD; Claudine Isaacs, MD; David Spetzler, PhD, MBAJune 22, 2015

John L. Marshall, MD: Hello. I am John Marshall, professor of medicine and director of clinical research at the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, DC. I want to welcome you to this edition of Medscape Oncology Insights, coming to you from the 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO), where the weather has just been terrible. It's freezing cold, there is a blustery wind—a nor'easter is coming through at the end of May.

What we are going to talk about today is genetic profiling. Molecular testing is everywhere. All of these companies are popping up. For almost every cancer that we take care of, there is some sort of additional genetic testing that is being done now. Is this broad molecular profiling essential to moving forward? Is it even advisable? Or is it, in fact, kind of unnecessary? We are getting a lot of these questions, and to help answer them, I have invited two good friends and world-class experts to come and discuss this with us. First is my good friend and long-time colleague, Dr Claudine Isaacs, professor of medicine and oncology, co-director of the Breast Cancer Program, and co-director of the Fisher Center for Familial Cancer Research at Georgetown University. Claudine, welcome. Thanks for joining us.

Claudine Isaacs, MD: Thank you.

Dr Marshall: And joining us is David Spetzler, who I recently met as we partnered through a bunch of projects. He is adjunct faculty in molecular cellular biology at Arizona State University in Tempe, and chief scientific officer at Caris Life Sciences in Phoenix. David, thanks for leaving the sunshine for this lovely Chicago weather. Thanks for joining us.

David Spetzler, PhD, MBA: Thank you.

Molecular Profiling: A User's Manual

Dr Marshall: What we are going to do is really drill down on two topics. First, we are going to pick apart molecular profiling. David, I am going to primarily pick on you for that. What does it mean? What are the different tests out there? I also want us to focus on what to do when we get these test results back. What do they mean? How do we use them? How do they affect patient care? How do I deal with these funny genetic mutations? We are going to cover all of that.

So, Dave, walk us through what most people know or have heard about next-generation sequencing. We know about some immunohistochemistry (IHC) tests for certain tumors. What do you think is the state of the art today? Walk us through some of the big tests.

Dr Spetzler: I think that the state of the art today is a combination of a multitude of technologies. When we evaluate the underlying molecular components of a cell, the components range from oligonucleotides and the genomic status of that cell to regulatory pathways of RNA, and finally to proteins and protein complexes.

Dr Marshall: Where do you think all of the answers are? Everybody is saying it's the DNA.

Dr Spetzler: I don't. I think that there are some clear answers in DNA, but for the most part, there are so many feedback mechanisms within the cell that we have to look much more broadly than that. If you look only at the DNA, then you are going to miss epigenetic alterations. You are going to miss regulatory components from RNA-induced silencing complexes. You are going to miss protein expression. Depending on how the proteins are assembling, you can have widely varying activity, and that is going to be key to understanding what is happening, especially in light of some of the new and exciting immunotherapies that are coming out.

Dr Marshall: I know that for colon cancer, we do some RAS gene testing as well as IHCs. In breast cancer, you have some standard tests for both genes and proteins, right? What is the standard profile today in breast cancer?

Dr Isaacs: Breast cancer is a little unusual because, for a while, we have been doing subtyping using standard immunohistochemistry and genetic analysis. We are using ER, PR, and HER2 as our standards. The question is, should we be doing more than that on metastatic sites?

Dr Marshall: But even for HER2, you use two different modalities.

Dr Isaacs: We tend to start off with immunohistochemistry and then we reflex to fluorescence in situ hybridization (FISH) if there is a result that gives us an indeterminate finding.

Dr Marshall: We pick on each other about this. We are still debating about which is the right way to test for HER2, aren't we?

Dr Isaacs: We are. Interestingly, in breast cancer, where we have been doing ER and PR testing for decades now, it took us until about 2 years ago for ASCO and the College of American Pathologists to come out with guidelines for how ER and PR should be performed and how we should interpret the results,[1] a test that we have been doing for decades.

Can You Trust Genetic Test Results?

Dr Marshall: As this new stuff is emerging, we often think of it as black and white, that the test is positive or negative. Talk to me a little bit about quality—tissue, tumor variability, all of those things. How reliable are these tests? can get widely differing results from what should essentially be the same underlying sample.

Dr Spetzler: It varies incredibly by laboratory. I think one of the key missing elements of molecular profiling is standardization of quality metrics across the entire industry. Everyone does it a little differently and everybody thinks about it a little differently, and depending on who you are working with, you can get widely differing results from what should essentially be the same underlying sample.

If we take, for example, the ER/PR question, testing of the incoming antibody lots is essential to a high fidelity result. Most people are relying on the manufacturer's quality control system, which often relies on just a recombinant protein test. I personally think that that is a very poor quality-control metric. Looking at a native system, looking at tissue lysate, and ensuring that that antibody has a high degree of specificity for its target is essential to interpreting the results properly. We actually perform a Western blot and then do confirmatory mass spectrometry on the antibodies that we use in clinical assays to be sure that we are hitting the right targets.

Dr Marshall: We have a couple of issues about tumor size. If you only have a very small amount of tumor, you are limited. Talk to me a little about the way tumors are stored. Most are formalin-fixed. How much of this stuff needs to be in fresh tissue? We see some assays that need to be fresh and some that can be formalin-fixed.

Dr Spetzler: It depends on the maturity of the technology. For the most part, we have been able to get the information out of formalin-fixed samples. It takes a little bit of extra work in preparation, but we can get good-quality results. There is definitely a risk for overfixation, where you end up with crosslinking of the nucleotides. That can inhibit your ability to amplify the DNA and get a good molecular result. But for the most part, I think we are doing a relatively good job of that.

Dr Marshall: What is the correct tumor descent in breast cancer? On a new diagnosis it is the primary, right?

Dr Isaacs: If you are doing molecular sequencing in breast cancer, you are typically doing that in the metastatic setting. We generally try to do a biopsy closest to the time that we are going to use those results. In breast cancer, there have been studies looking at changes to the standard evaluations that we do—looking from the primary to metastatic site—that show that ER, PR, and HER2 status can change.[2,3] As we use even broader testing to examine many more genes and proteins, it makes sense to look at the most proximate biopsy to make determinations.

Dr Marshall: And how often would you do that in breast cancer? Just once with metastatic disease, or are you finding that it might be logical for patients who have had several years of survival with metastatic disease to do that more than once?

Dr Isaacs: If we are going to be using next-generation sequencing techniques or various broader looks at the tumor, we really want to get the information closest to the time when we will be either changing therapy on the basis of that molecular testing or using the testing as one more piece in the jigsaw puzzle for making a decision about what to do next. My own recommendation is that if we are going to do testing, we should do it close to the time that we are going to be making a decision.

Dr Marshall: We in colon cancer have been a little slow because we have had this belief that, say for RAS testing, the primary is the way it is always going to be, but my experience over the past year or so is that the more testing we are doing,[4] the more we are seeing changes. One of the pushbacks we always get about this type of testing is tumor variability. Studies have looked at isolated balls of tumor and seen different profiles from different segments.[5] How are we going to deal with that variability in making therapeutic decisions?
Gregory D. Pawelski
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Old 07-20-2015, 02:00 PM
gdpawel gdpawel is offline
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Blood-Based Biopsy to Aid Therapeutic Decisions

Dr Spetzler: That is a very tough question. One of the things that we can do is look at the underlying structure of the tissue and try to profile the multitude of clones that are present. But relying on tissue for that is going to be a flawed approach. We eventually have to get to a blood-based biopsy-type technology that is capable of looking at all of the clones that are present in the cancer.

Dr Marshall: Is this the circulating cancer cell? There is a lot of work like that in breast cancer. Is that what you are thinking?

Dr Isaacs: Yes. People are looking typically at circulating cancer cells within the setting of clinical trials to try to evaluate their utility.

Dr Marshall: I always wonder which cells living in the blood are actually reflective of the tumor. Give us some of the newer technologies that are being explored—how we are going to measure the blood and what we are going to measure in the blood.

Dr Spetzler: Aside from circulating tumor cells, there is certainly opportunity to exploit circulating microvesicles that are going to be shed into circulation much earlier in the cancer event. That is going to be a critical component, because if you have to wait until there is metastatic disease to begin to get that type of real-time feedback, it is going to be less useful than if we can get the information early. Then we can really start to make meaningful contributions to treating patients.

Dr Marshall: I struggle with how we are going to figure all of this out. We can order these tests and get these answers back. We need to work together to figure out the answers to all of this. There are various groups forming—we are forming one ourselves—to try to work collectively. What is the magnitude of the number of patients and amount of data? How big does the haystack have to be in order for us to find these needles?

Dr Spetzler: It is huge. If you do the math for 55 drugs with 60 biomarkers, even assuming equal prevalence of them, you need 2 million patients in order to be powered to assess an individual biomarker's correlation to an individual therapeutic. The days of randomized trials are quickly going to go away because it is just mathematically infeasible to accomplish it. I think performing observational evaluations and analyses are the only things that we can do. It is going to take a concerted effort to track not only the underlying profile, but also the patient's treatment history and final outcome. By combining all of our data, we can begin to have a chance at this, but it is going to take a village. It is not going to be done by any one person or any one group alone.

Dr Marshall: Claudine, I know you and I have been thinking a lot about this. How are we going to apply this broad molecular testing in the clinic and use it? My experience with most oncologists is that they have been doing this testing as an attempt to find an extra therapy. They go through the standard lines of therapy, the patient is still doing okay but has metastatic disease, and they're looking for something more. Tell me your thoughts about this and also about how we could move this more proximally in breast cancer, colon cancer, and other diseases, where it might help guide us away from empirical therapy and more toward molecularly targeted therapy.

Best Uses for Molecular Profiling

Dr Isaacs: In breast cancer, where we have volumes of data on what to do in certain situations, we need to be a little careful and make sure that at least in the first couple of lines of therapy, we are being guided by well-conducted clinical trials. Once we get to the point where we care whether it is treatment A or treatment B and the umpteen other factors that go into it—patient preference, comorbidity—we can certainly use this technique as another piece of that puzzle to help push us.

We have also been using it when we think about phase 1 trials. We are looking at new drugs because there is a plethora of clinical trials that are using good standard agents, but they are adding some targeted therapies. It allows us to try to figure out whether this trial might make more sense for this particular patient based on the profile that we are seeing.

Dr Marshall: Yes, I think that is a great setting. If you have choices and you are unsure, can these tests help guide us? And then we also have the other piece. We are seeing a lot of this in gastrointestinal cancer. In fact, we are seeing some of this at the meeting. We are finding targets like HER2 in colon cancer.[6] Not a huge number, but 5%-7% of colon cancers is a lot of colon cancer. That is higher than the percentage of ALK-positive lung cancer. Do you see that there may be some value in finding those targets? What level of evidence do you think you would need to say that, because a trial showed a particular benefit rate, we should get that drug extended to those types of patients?

Dr Isaacs: For targets in breast cancer, there have been many studies that have validated certain measures, and those are the measures that actually showed us that particular therapies were effective. I think that we need to be careful if we have a tumor that is repeatedly HER2 negative by standard evaluation and then, all of a sudden, it turns up HER2 positive. We need to do a little due diligence and make sure. We also recognize that tumors have different clones, and that you might indeed have a clone now that you didn't recently biopsy that is HER2 positive.

With Antibodies, You Don't Always Get What You Pay for

Dr Marshall: Okay. That's great. So, David, the talk at this meeting was about immune therapy, and your company may be the only one that has a commercial assay for measuring PD-1 and PD-L1. There is a lot of talk about whether this is the right biomarker or not. We have positive trials and we have negative trials. Talk to me about this target and tell me your opinion about whether or not we should be measuring it. Why are we getting variable results from various trials?

Dr Spetzler: There are a couple of different components to that answer. First, of course, is the underlying quality of the antibody that is being used in the assay.

40% of the antibodies we can buy off the shelf actually bind to a different target than what is on the label of the bottle.

Dr Marshall: I am an oncologist. I don't know why that matters. I think antibodies are perfect and they all work the same.

Dr Spetzler: It is a little shocking to realize that when we order antibodies and test them, we find that about 40% of the antibodies we can buy off the shelf actually bind to a different target than what is on the label of the bottle.

Dr Marshall: So the antibodies that you would use in a Clinical Laboratory Improvement Amendments lab are that variable?

Dr Spetzler: They are that variable. When we get additional lots of the same underlying clone, about 25% of the time there is a perturbation in the performance of that particular lot of antibody. They are incredibly sensitive to changes in purification, storage, or underlying buffer content.

Dr Marshall: Is that true for all of them or is it true for the ones that are newer and that haven't been ironed out quite as well?

Dr Spetzler: RUO antibodies are research-use-only. There are ASR antibodies, which are analyte-specific reagents, and then there are FDA-approved antibodies. As you climb up that regulatory chain, you get an increase in reliability.

Dr Marshall: How do oncologists know what they are getting?

Dr Spetzler: If they don't ask the question, they probably don't know what they are getting.

Dr Marshall: Many times, oncologists aren't making the decision about who is doing the test. The test can be done locally in their own pathology labs or wherever their healthcare system has contracted. Is that right?

Dr Spetzler: That is right.

We need to learn to question our lab results.

Dr Marshall: So, what we need to do is—just like we do when we get radiology reports that say "new nodule, can't rule out cancer"—learn to question our lab results, particularly as these new molecular tests come forward.

Dr Spetzler: Without question.

Dr Marshall: Now let's drill down on the PD-1, PD-L1 story a little bit.

Dr Spetzler: If you assume that some of the negative results are a result of poor quality control, then that makes the positive results a little more enticing. Of course, the alternative could be just as true. What if there is a perturbation—it is not actually hitting the PD-1 or PD-L1—and that is what is showing the positive result? It comes back to needing an aggregation of all the data elements to be able to fully understand what is happening. As you evaluate the intercalating leukocyte and its binding partner on the surface of a tumor, there can be an interaction there. Is it the number of leukocytes expressing these proteins that is actually what is going to determine whether there is a good response or not?

I think we are at a point where we have a lot of questions. We don't necessarily have a lot of answers. For me, it is all about facilitation of exploration of these data elements. Some of them are going to turn out to be good, some of them are going to turn out to be bad. But unless we start to cohesively understand what is out there, we are not going to be able to figure out which is which.
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Old 07-20-2015, 02:03 PM
gdpawel gdpawel is offline
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Tales of the Unexpected Mutation

Dr Marshall: That brings us to the next topic. When you do a broad profile, 600 genes and all of this IHC, what is research and what is practice? Claudine, I have been down to your office several times with a report of some patient who has some funny BRCA mutation or the like. We are getting unexpected mutations, and I, as an oncologist, go back to the chart and look at the family history. Did I miss something? How are we going to deal with all of this new stuff that we are going to find, the needles in the haystack that might mean something but might not?

Dr Isaacs: Finding what is suggestive of a germline genetic mutation, not a somatic mutation in the tumor tissue, is something that we need to be increasingly prepared for. As we start to do more and more of this testing, we are going to find unexpected mutations and tumor types that we weren't considering as part of the spectrum. It is quite clear that we need to be prepared for that. Whenever somebody sends off one of these tests, they need to be prepared for something that might not be what they anticipated and that could be reflective of a hereditary predisposition to cancer. Not only does it affect the individual that you are testing, but it could have profound implications for their family members, too. Before you send the test, it is important to discuss with the patient that there might be an unexpected finding. There are some suggestions that you should take a broader family history and tell the patient if there is a suggestive family history. "Maybe we will find something on your tumor. How will we handle this?"

If you find something unexpected, there are clear recommendations from the American College of Medical Genetics.[7] They recommend that if you find an incidentally found mutation that predisposes the patient to a number of hereditary syndromes—many of them are hereditary cancer syndromes—you have a duty to disclose that to the patient. You need to be prepared for that. You should probably be prepared to have a genetic counselor around to help you. Many people are creating molecular tumor boards that include a broad group of clinicians and molecular and medical geneticists, or a genetic counselor, to help wade through that process.

Another issue that often comes up: We do this testing as people are approaching the end of their life. What happens if you find a BRCA1 mutation and the person that you did the testing on is deceased? You have a piece of information that could have very profound implications for that person's family members.

Dr Marshall: Yes, this is potentially charged information. I want to make sure that I understand this. When you or molecular companies get tissue, you are actually purposely testing the tumors. You select out the tumor.

Dr Spetzler: We do.

When in Doubt, Call in a Genetic Counselor

Dr Marshall: The tumor might have a BRCA mutation, but the germline may not. When we get this test back, we need to remember that the result is for the tumor, right? What would you advise if you got that [a test result showing a BRCA mutation]? Does the patient go straight to a genetic counselor? Do I get him to spit in a cup and send it off to 23andMe? What do I do at that point?

If you see BRCA1 or BRCA2, what you need to do is confirm it with germline testing.

Dr Isaacs: I would recommend, if it's possible, involving a genetic counselor in that process. Some genes are those that you associate with hereditary cancer syndromes. They are frequently mutated in the tumor and they reflect a somatic change. An example is CDH1, which is associated with hereditary diffuse gastric cancer. Most of the times that you see a CDH1 mutation, it is not due to an inherited predisposition but to a somatic mutation in the tumor. That is much more common. If you see BRCA1 or BRCA2, what you need to do is confirm it with germline testing, and I would recommend that you involve a genetic counselor in the process.

Dr Marshall: Any further comment on that?

Dr Spetzler: One component of that is a greater understanding of the underlying molecular data that are being created. Something that might help resolve this without additional cost to the system is an evaluation of the variant frequency of the mutation that is found. If you find a BRCA mutation but it has a 14% variant frequency, the probability that it is a germline alteration becomes very, very low. The risk to the family is now significantly diminished. That might change the decision-making process about when to involve a genetic counselor. That is a level of information that is not typically shared but should be.

Dr Isaacs: I think the point that you are making is that many of the changes that we find when we send off for what we think is genetic testing are, in fact, variants that are of no significance whatsoever. They are benign polymorphisms, and we need to be able to triage that. At present, it is hard to tell from the report what that is, and that is why I think it is important to involve the genetic counselor, so people don't think that they have a mutation. If they had sent it off for germline testing, it would have been reported as a negative result.

Dr Spetzler: I couldn't agree more.

Dr Marshall: One of the most common questions that I get about this is: "I have an ALK mutation in colon cancer. How can I get crizotinib (Xalkori®) and who is going to pay for it?"

I don't have a quick-and-dirty answer to that, other than that some companies will pay. If you ask, some insurance companies and payers will pay for it. ASCO has really taken this on. Richard Schilsky has a very nice position paper[8] on what we would like to happen, which is a partnership between genetic companies; patients; the industry, who would be sponsoring the drug; and regulatory bodies to study the drug. A patient could get crizotinib in exchange for information on the outcomes. The more we build these networks and the more we measure the outcomes, the more likely we can prove that these drugs have activity in these settings.

For the folks out there who are ordering these tests and feeling frustrated because they're getting back answers that don't really help, or those with a fear about payment, I think there is policy change on the way that is going to improve those.

Claudine, David, I want to thank you for taking time out of your busy ASCO schedule to come and talk about this very important subject of molecular profiling. It is my hope, at least, that incorporating this kind of testing will not only improve outcomes but also bring better value—meaning that it will allow us to do a better job, have less toxicity, and have better outcomes for our patients.

Again, thank you for joining us. And thank you guys for joining us in this edition of Medscape Oncology Insights. This is John Marshall, reporting from ASCO 2015.


Hammond MEH, Hayes DF, Dowsett M, et al. ASCO-CAP guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784-2795. [url]

Macfarlane R, Seal M, Speers C, et al. Molecular alterations between the primary breast cancer and the subsequent locoregional/metastatic tumor. Oncologist. 2012;17:172-178.

Arslan C, Sari E, Aksoy S, Altundag K. Variation in hormone receptor and HER-2 status between primary and metastatic breast cancer: review of the literature. Expert Opin Ther Targets. 2011;15:21-30.

Kim R, Schell MJ, Teer JK, et al. Co-evolution of somatic variation in primary and metastatic colorectal cancer may expand biopsy indications in the molecular era. PLoS One. 2015 May 14.

Kreso A, O'Brien CA, van Galen P, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339:543-548.

Siena S, Sartore-Bianchi A, Lonardi S, et al. Trastuzumab and lapatinib in HER2-amplified metastatic colorectal cancer patients (mCRC): The HERACLES trial. Program and abstracts of the American Society of Clinical Oncology Annual Meeting; May 29-June 2, 2015; Chicago, Illinois. Abstract 3508.

Hampel H, Bennett RL, Buchanan A, Pearlman R, Wiesner GL. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. ACMG Practice Guidelines American College of Medical Genetics and Genomics [url] ancer_predisposition.pdf

Tsimberidou AM, Eggermont AM, Schilsky RL. Precision cancer medicine: the future is now, only better. Am Soc Clin Oncol Educ Book. 2014; 61-69.

Citation: John L. Marshall, Claudine Isaacs, David Spetzler. The Frightening Truth About Genetic Testing. Medscape. Jun 22, 2015.
Gregory D. Pawelski
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Old 07-20-2015, 02:15 PM
gdpawel gdpawel is offline
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Default Tests for New Cancer Drugs Not Reliable Enough, Doctors Say

CHICAGO (Reuters) - Drugmakers including Bristol-Myers Squibb Co and Merck & Co are testing which patients will most benefit from new cancer treatments based on a protein found in their tumors, but that biomarker may be too unreliable, researchers and health experts said.

Bristol's Opdivo (nivolumab) and Merck's Keytruda (pembrolizumab) are both therapies designed to block Programmed Death receptor (PD-1) that tumors use to evade the body's natural defenses. Competitors Roche Holding, AstraZeneca and Pfizer also have similar drugs in an earlier stage of development. The drugmakers are conducting clinical trials that test patient tumors for a related protein called PD-L1.

The new drugs are mainly aimed at patients with solid tumors suffering from diseases including lung cancer and liver cancer. Lung cancer, the most common type, claims 1.8 million new cases each year worldwide. Sales of drugs to block PD-1 could reach $33 billion a year by 2022, according to Morningstar.

New data published on Friday showed that Opdivo was most helpful to lung cancer patients with the highest levels of PD-L1 in their tumors, adding to evidence of a link. That would suggest that doctors routinely test for the protein before giving a patient Opdivo. The approach is already used for some cancer drugs that are prescribed only if a patient has a specific genetic mutation.

Cancer experts interviewed by Reuters at the American Society of Clinical Oncology meeting in Chicago, however, said that use of protein levels in a tumor as a guide for treatment cannot be counted on in the same way as a genetic variation.

Test results can vary depending on which part of the tumor was biopsied and the degree to which the cancer has spread. In addition, tests developed by drugmakers don't follow the same standards.

So while clinical trials show that drugs like Opdivo and Keytruda work best in people who test positive for PD-L1, some patients who test negative have benefited from the treatment.

"We shouldn't withhold immunotherapy from patients based on a biomarker yet," said Dr Roy Herbst, chief of medical oncology at Yale Cancer Center in New Haven, Connecticut, referring to Opdivo. "We don't even know if PD-L1 is the right biomarker."

Dr. Richard Pazdur, the U.S. Food and Drug Administration's oncology chief, also cautioned that there is still a great deal of uncertainty about how to best measure for PD-L1.

"The key issue is whether the biomarker is essential for safe and effective use of the drug," Pazdur said. "If not, then it is probably not going to be an essential element in the indications for the drug. But it would be useful information."


Health insurers would also be keen to have a surefire test of when a novel, and expensive, cancer drug is most likely to work. Treatment with Opdivo or Keytruda alone costs about $12,500 a month in the United States, or $150,000 a year.

Pfizer's Xalkori (crizotinib), another new, expensive drug, is approved by the FDA only for patients with a mutation of the ALK gene. A diagnostic test must be used to identify the estimated 4% of patients with non-small cell lung cancer who are likely to improve using Xalkori.

Current approvals for PD-1 drugs do not require tumor testing. Bristol's Opdivo was approved by the FDA in December to treat advanced melanoma. In March, it was cleared to treat a form of lung cancer, giving Bristol an early advantage in the much larger market. Merck's Keytruda has been approved for advanced melanoma since September and is awaiting approval as a lung cancer treatment.

Another confounding factor is that drugmakers are combining Opdivo and Keytruda with other treatments to boost their effect, from well-established medications like chemotherapy to experimental compounds.

In a small trial of patients with advanced lung cancer, AstraZeneca's experimental PD-L1 antibody, MEDI4736, was given in combination with tremelimumab, which targets a different immune system inhibitor. Nearly half of patients who were negative for PD-L1 responded to the treatment.

"It seems like the PD-L1 negative patients are now responding as well," said Bahija Jallal, executive vice president at AstraZeneca's MedImmune unit. "That was the whole point of doing the combination."

A Bristol-Myers trial found melanoma patients whose tumors contained PD-L1 fared just as well with Opdivo alone as with a combination of Opdivo and a second immunotherapy, Yervoy (ipilimumab). But patients without PD-L1 detected in their tumors lived more than twice as long without their disease getting worse when treated with both drugs.

Around 80% of melanomas test positive for PD-L1, compared with around 50% of lung cancers, said Eric Rubin, Merck vice president, global clinical oncology. At the same time, levels of PD-L1 are not static.

"If I check it today, it might change tomorrow. It might be different in one area of the tumor than in another area," said Dr. Richard Carvajal, director of melanoma service at Columbia University Medical Center in New York.

Drug companies are working to refine and standardize their PD-L1 testing, as well as exploring other ways to identify which patients will benefit from immunotherapies.

Data presented at ASCO showed that Opdivo helped patients with certain cancers, including colon cancer, whose tumors exhibited an uncommon defect in genes needed for DNA repair. Drugmakers are also trying to discover if there are any negative biomarkers to indicate which patients should not be treated with immunotherapies.

"We are taking account of how the immune system is interacting with the tumor. It's a completely different type of biomarker and understanding," said Sandra Horning, chief medical officer at Roche's Genentech unit.

Citation: Tests for New Cancer Drugs Not Reliable Enough, Doctors Say. Medscape. Jun 02, 2015.
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Old 09-05-2015, 02:38 AM
gdpawel gdpawel is offline
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Default Making Genomics Routine in Cancer Care? Gene Tests vs Cell Culture Tests

Cancer researchers are rapidly discovering new mutations that predict a particular patient's prognosis, or supposedly how that patient's cancer will respond to drugs. But doctors don't routinely use even the most basic genetic tests.

While academic medical centers are often good at implementing the latest diagnostic tests, the problem is that 70 - 85 percent of cancer patients in the United States get their care at community clinics rather than at academic medical centers. That kind of testing and decision making is not available within community oncology centers.

It is thought that in lung cancer alone, there are eight to ten genetic mutations that can determine what drugs are most likely to work. In one type (NSCLC), genetic testing for mutations in a gene known as EGFR supposedly can predict whether the patient will respond to a certain class of drugs. But only about a quarter of patients get this molecular testing.

Then there is the problem with the way insurers pay for cancer care. Academic centers are often funded through grants, while physician and local hospital-owned oncology clinics often make income based on profit from prescription cancer drugs. That means they have little incentive to implement genetic tests that may limit the number of patients that receive the cancer drugs. If they do, they make less money.

It is being proposed that rather then paying per test or per drug, insurers pay per episode of care, incorporating all aspects of treatment. For some reason, it is thought that molecular testing could decrease the overall cost of care, because expensive medicines won't go to people who are unlikely to respond.

Now, profit is a powerful motivating force. Among private payors, the profit motive is entirely consistent with the goal of diagnostic testing, which is to identify efficacious therapies irrespective of drug mark-up rates.

And everyone is scared to death at what is going to happen to the healthcare economic system with increasingly expensive new drugs that benefit only a small percentage of patients who receive these genomically-derived cancers.

Hence the headlong rush to develop companion (molecular) diagnostic tests to identify molecular predisposing mechanisms whose presence still does not guarantee that a drug will be effective for an individual patient.

The pressure, in fact, is so great that these molecular companion diagnostics they've approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various targeted therapies. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

The problem with all of this is that gene and protein testing are indirect approaches to chemotherapy selection which examine a single process within the cell or a relatively small number of processes. Their aim is to determine only if these is evidence of a theoretical predisposition to drug susceptibility. In this regard, molecular testing is a "static profiling" approach.

In contrast, a "functional profiling" approach involves real-time assessment of living cancer and endothelial cell behaviors in the presence or absence of anti-cancer or anti-angiogenic drugs. This method accounts not only for the existence of genes and proteins but also for their functionality and for their interaction with other genes, other proteins, and other processes occurring within the cell.

What is an excellent feature of this protocol for cancer patients is "real-time" reporting of patient outcomes by the patients' doctors as they become available. This is in sharp contrast to a traditional clinical trial, where outcomes take years to accumulate in large cancer trials.

This represents a potential landmark change in approach to personalized cancer treatment. The kind which has the potential to change the tide of cancer treatment. One which being the ability to direct cancer treatments to personal tumors rather than groups of patients' tumors. This has the potential to bring about "cutting edge" personalized cancer treatment proposals.
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Old 09-05-2015, 02:41 AM
gdpawel gdpawel is offline
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Default Chemosensitivity Misnomer

'Chemosensitivity testing' is sometimes misunderstood. I just want to explain the differences in assay methodologies. The phrase 'chemosensitivity assay' has been used out of context by a lot of people. There is molecular profiling (genomic/proteomic analysis) and there is functional profiling (cell function analysis). The former testing (genotype) is theoretical and the latter (phenotype) is actual.

In drug selection, molecular (genetic) testing examines a single process within the cell or a relatively small number of processes. The aim is to tell if there is a theoretical predisposition to drug response. It attempts to link surrogate gene expression to a theoretical potential for drug activity. Patients' cancer cells are never exposed to chemotherapy drugs. It relies upon a handful of gene patterns which are thought to imply a potential for drug susceptibility. In other words, molecular testing tells us whether or not the cancer cells are potentially susceptible to a mechanism or pathway of attack. It doesn't tell you if one drug is better or worse than another drug which may target a certain mechanism or pathway.

Functional profiling doesn't dismiss DNA testing, it uses all the information, both genomic and functional, to design the best treatment for each individual, not populations. Cell culture assay laboratories test for a lot more than just a few mutations. The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. One needs to analyze the systems' response to drug treatments, not just a few targets (mechanisms or pathways).

The functional profiling test (a 'real' chemosensitivity test) assesses the activity of a drug upon combined effect of all cellular processes, using several metabolic (cell metabolism) and morphologic (structure) endpoints, at the cell 'population' level, rather than at the 'single cell' level, measuring the interaction of the entire genome.

Examining a patient's DNA can give physicians a lot of information, but as the NCI has concluded (J Natl Cancer Inst. March 16, 2010), it cannot determine treatment plans for patients. It cannot test (chemo) sensitivity to any of the targeted therapies, just 'theoretical' candidates for targeted therapy.
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Old 09-13-2015, 06:15 PM
gdpawel gdpawel is offline
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Default Another Hiccup in Cancer Genomics Testing

Robert A. Nagourney, M.D.

Elon Musk, the founder of Google, once said, "It’s okay to have your eggs in one basket, as long as you control what happens to that basket." This was brought to mind by a recent article in the New England Journal of Medicine entitled “Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutation”. The study tested whether genetic pre-screening could provide high response rates for Vemurafenib in patients who were found BRAF-mutation positive. That is, the target of the drug.


As Vemurafenib, FDA-approved for BRAF mutated malignant melanoma provided response rates up to 50% in this disease, it was reasoned that this could be replicated in other cancers that carried the same BRAF gene target. Using a study design known as a “basket trial”, 122 patients with a variety of cancers who were found (+) for BRAF mutation were offered the drug. Again, only patients found (+) for BRAF could accrue. This enriched the pool, ensuring the highest probability of clinical success. It was hoped, I dare say expected, that response rates similar to melanoma would be observed.

The results were underwhelming. Much to the chagrin of the authors, only 18 of the 75 patients treated had objective responses (24%) While better responses were observed in lung cancers (42%) and a very rare form of cancer known as histiocytosis (43%), the response rate in all other cancers, even after careful preselection was only 9.5%. More troubling was the fact that only 1/27 (4%) colorectal cancers showed objective response, even after Erbitux was added to the mix. Similarly only 1 of 8 biliary and 1 of 7 thyroid cancers responded, again after careful genomic pre-screening.

This prompted a certain amount of navel-gazing on the part of the authors, who stated "an important implication is that conventional tumor nosology based on organ site cannot be entirely replaced by molecular nosology." They continued, these data present a challenge to clinicians who want to make treatment decisions on the basis of tumor genomic profiling."

While human genomics has progressed rapidly, providing insights into many diseases and some treatments, the field has suffered from over exuberance manifested in the widely held belief that genomic analyses hold the key to all medical problems, big and small.

These favorable results in lung cancer and histiocytosis are encouraging but will need confirmation. Meanwhile, the numerous commercial entities, universities, and national institutions that tout genomic profiling as the panacea for cancer must continue to confront the painful reality that human tumor biology is more complex than the sum of its genes.

Cancer is a disease of context and as the accompanying editorial points out "One bio-informaticist's driver mutation is another's passenger mutation." This speaks to the fact that the presence of a mutation is but one factor in the broader disease process that drives cancers. Functional analyses based on phenotype (the observable properties of an organism that are produced by the interaction of the genotype and the environment) can interrogate the importance of a given genetic abnormality. Many alterations present in tumors may have no impact on their behavior. Only through the careful study of cancer phenomics and cellular responses will targeted agent activities be accurately determined. We believe this establishes the pressing need to incorporate phenotypic, as well as genotypic, analyses in the study of human cancer.
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